Translational medicine in inborn errors of metabolism and other rare genetic diseases
Research summary:
Inborn errors of metabolism (IEM) are a large group of rare genetic diseases, including any condition in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Nevertheless many of them detected by standard biochemical test are not genetically solved. In addition, many of them lack a definitive therapy. In this context, our objectives, aligned with the worldwide aims in translational research in rare diseases, are addressed to improve the knowledge of IEM towards tailored treatments. First, our activity is aimed to the identification of new genes causing pathology using a combination of "omics" tools (genomic, transcriptomic and metabolomic technologies) and cellular biology techniques, in order to decipher the effect of altered genes and to identify novel pathological processes. Specifically, we are working on the identification and characterization of genetic defects involved in the process of glycosylation and protein transport (CDG syndrome), as well as in other diseases related to mitochondrial dysfunction or neurological disorders due to cerebral glucose transport deficiency, among others. We are also involved in the development of specific therapeutic strategies targeted to the mechanism of action of the mutations detected in neurometabolic diseases in the era of the personalized medicine. To that end, we are specifically involved in the development of therapies designed to rescue defects affecting protein folding, an extended mechanism in many IEM. For preclinical studies and for searching additional therapeutic targets based on pathophysiology studies we are working in the generation of disease cellular models obtained from reprogramming of patient derived fibroblasts and subsequent differentiation into hepatocytes, neurons or other tissues more relevant to the disease. In a later preclinical stage we intend also to use hepatic and cerebellar organoids to validate the potential drugs before testing in the adequate animal models.
This project is funded by the following grants: ISCIII (PI16/00573), CIBERER (ER18TRL746), Comunidad de Madrid (B2017/BMD3721) y Fundación Isabel Gemio in collaboration with La Obra Social de la Caixa (LCF/PR/PR16/11110018).
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Arribas Carreira | Laura | 220 | 4596/7830 | laura.arribas(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Profes. GP1 |
| Gallego Martínez | Diana | 220 | 4596/7830 | Titulado Sup.de Actividades Técn. y Profes. GP1 | |
| Gámez Abascal | Alejandra | 220 | 4596/7830 | agamez(at)cbm.csic.es | Profesor Contratado Universidad, GA |
| Leal Pérez | Mª Fátima | 220 | 4566/7830 | fleal(at)cbm.csic.es | Contratado CIBER |
| Navarrete López de Soria | Rosa María | 220 | 4566/7830 | rnavarrete(at)cbm.csic.es | Contratado CIBER |
| Pérez González | Belén | 220 | 4566/7830 | bperez(at)cbm.csic.es | Profesor Titular Universidad, GA |
| Rodríguez Pombo | Pilar | 220 | 4628 | mprodriguez(at)cbm.csic.es | Profesor Titular Universidad, GA |
| Soriano | Alejandro | 220 | 4560/7830 | ||
| Vilas Lagoa | Alicia | 220 | 4560/7830 | alicia.vilas(at)cbm.csic.es | Titulado Sup.de Actividades Técn. y Profes. GP1 |
Relevant publications:
- Bravo-Alonso I, Navarrete R, Vega AI, Ruíz-Sala P, García Silva MT, Martín-Hernández E, Quijada-Fraile P, Belanger-Quintana A, Stanescu S, Bueno M, Vitoria I, Toledo L, Couce ML, García-Jiménez I, Ramos-Ruiz R, Martín MÁ, Desviat LR, Ugarte M, Pérez-Cerdá C, Merinero B, Pérez B, Rodríguez-Pombo P. “Genes and Variants Underlying Human Congenital Lactic Acidosis-From Genetics to Personalized Treatment”. J Clin Med. 2019 Nov 1;8(11). pii: E1811. doi: 10.3390/jcm8111811.
- Arribas-Carreira L, Bravo-Alonso I, López-Márquez A, Alonso-Barroso E, Briso-Montiano Á, Arroyo I, Ugarte M, Pérez B, Pérez-Cerdá C, Rodríguez-Pombo P, Richard E. "Generation and characterization of a human iPSC line (UAMi005-A) from a patient with nonketotic hyperglycinemia due to mutations in the GLDC gene”. Stem Cell Res. 2019 Aug;39:101503. doi: 10.1016/j.scr.2019.101503.
- Navarrete R, Leal F, Vega AI, Morais-López A, Garcia-Silva MT, Martín-Hernández E, Quijada-Fraile P, Bergua A, Vives I, García-Jiménez I, Yahyaoui R, Pedrón-Giner C, Belanger-Quintana A, Stanescu S, Cañedo E, García-Campos O, Bueno-Delgado M, Delgado-Pecellín C, Vitoria I, Rausell MD, Balmaseda E, Couce ML, Desviat LR, Merinero B, Rodríguez-Pombo P, Ugarte M, Pérez-Cerdá C, Pérez B. “Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program”. Eur J Hum Genet. 2019 Apr;27(4):556-562. doi: 10.1038/s41431-018-0330-0.
- Coughlin CR 2nd, Swanson MA, Kronquist K, Acquaviva C, Hutchin T, Rodríguez-Pombo P, Väisänen ML, Spector E, Creadon-Swindell G, Brás-Goldberg AM, Rahikkala E, Moilanen JS, Mahieu V, Matthijs G, Bravo-Alonso I, Pérez-Cerdá C, Ugarte M, Vianey-Saban C, Scharer GH, Van Hove JL. “The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT”. Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Erratum in: Genet Med. 2018 Jan 04
- Ortigoza-Escobar JD, Alfadhel M, Molero-Luis M, Darin N, Spiegel R, de Coo IF, Gerards M, Taylor RW, Artuch R, Nashabat M, Rodríguez-Pombo P, Tabarki B, Pérez-Dueñas B; Thiamine Deficiency Study Group. “Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors”. Ann Neurol. 2017 Sep;82(3):317-330. doi: 10.1002/ana.24998.
- García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjós M, Vilaseca MA, Ormaizabal A, Pristoupilova A, Agulló SB. “Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients”. Hum Mutat. 2014 Apr;35(4):470-7. doi: 10.1002/humu.22513.
- Oyarzabal A, Martínez-Pardo M, Merinero B, Navarrete R, Desviat LR, Ugarte M, Rodríguez-Pombo P. “A novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease”. Hum Mutat. 2013 Feb;34(2):355-62. doi: 10.1002/humu.22242.
- New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. BBA, Molecular Basis of Disease(2018) 1864(2):640-648.
- Generation and characterization of two human iPSC lines from patients with methylmalonic acidemia cblB type. Stem Cell Research (2018) 29:143-147.
- Protein misfolding diseases: prospects of pharmacological treatment. Clin Genet. 2017 Jul 3. doi: 10.1111/cge.13088. Review.
- A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis. J Pediatr. 2017 Apr;183:170-177.
- Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease. Hum Mutat. 2017 Jun;38(6):678-691. doi: 10.1002/humu.23208. Epub 2017 Mar 20.
- Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. Hum Mutat. 2017 Feb;38(2):160-168. doi: 10.1002/humu.23138. Epub 2016 Nov 21.
